The invention relates to the use of perfluoroalkyl-containing metal complexes that have a critical micelle formation concentration of  less than 10xe2x88x923 mol/l, a hydrodynamic micelle diameter (2 Rh) greater than 1 nm and a proton relaxivity in plasma (R1) greater than 10 l/mmolxc2x7s as contrast media in MR-imaging both for visualization of plaque, lymph nodes, infarcted and necrotic tissue and for independent visualization of necrotic tissue and tumor tissue. It has been shown that perfluoroalkyl-containing metal complexes with the above-mentioned properties are extremely well suited for the independent visualization of plaque, tumors and necroses with the aid of MR-imaging and simultaneously can also cover the diagnostically important area of infarction and necrosis imaging.
Arteriosclerosis is the most important and most frequent pathological alteration of arteries with hardening, thickening, loss of elasticity and lumen constriction. It represents the most frequent cause of death in Western industrialized countries. Vascular wall alterations are produced by lipid retention, connective tissue reproduction and calcification with irregular dispersion for wall instability, vascular stenosis and for storage of clots. Causes of disease are numerous exogenic and endogenic noxae or diseases, e.g., hypertonia, hyperlipidemia, hyperfibrinogenemia, diabetes mellitus, toxins, nicotine, antigen-antibody complexes, inflammations, hypoxia, mental stress, age and family stress. The latter result in the disruption of the integrity of the vascular inside wall, in the disruption of growth control of smooth muscle cells of the vascular wall and in impairing the degradation of aged cell components. Treatment of arteriosclerosis itself is not possible; the target of medical efforts is prevention by reducing risk factors, e.g., using lipid reducing agents.
The diagnosis of arteriosclerosis in clinical practice is currently carried out mainly by angiography as a gold standard. The limitation in all processes that are based on the measurement of the reduction of the vascular lumen is, however, the early stage of the disease, which is characterized by a thickening of the vascular wall in the case of a normal vascular lumen (Glagov, S., Zarins, C. K. Quantitating Atherosclerosis. In: Bond, M. G.; Insull, W.; Glagov, S.; Chandler, A. B.; Cornhill, J. F. (eds.). Clinical Diagnosis of Atherosclerosis. Quantitative Methods of Evaluation. New York: Springer-Verlag, 1983, 11-35). Another method for diagnostic assessment of vascular wall and vascular lumen is the intravascular or percutaneous ultrasound.
Magnetic nuclear spin resonance tomography (MRT) is a modem, non-invasive radiological process, which makes possible the visualization of physiological and pathophysiological structures with a very good space and time resolution. The use of specific contrast media with selective concentration in certain tissues and organs can increase the diagnostic value considerably in this case. Contrast medium preparations with selective concentration in arteriosclerotic plaque were able to detect location and degree of the disease at an early time and thus to make possible a targeted therapy and prophylaxis, and therefore the search for suitable contrast media began early.
Thus, hematoporphyrin derivatives are claimed in U.S. Pat. No. 4,577,636 as contrast media for the detection of atherosclerotic plaque. As methods, scintigraphy, radiography, fluorescence and, for paramagnetic metalloporphyrins, even NMR-spectrometry, are mentioned. As paramagnetic ions, Gd, Cr, Co, Ni, Ag and Eu are cited.
The disadvantage to these compounds is that the porphyrins are stored in the skin and cause discolorations that can last up to several weeks. Moreover, they result in a photosensitization. In addition, the danger exists that in a long retention time in vivo, the metalloporphyrin loses the metal.
In Application WO 95/09856, metalloporphyrins (deuteroporphyrins) are claimed for diagnosis and therapy of plaque. As a diagnostic method, MRI is mentioned. These porphyrins also cause discolorations of the skin. in Application WO 95/09013, conjugates that consist of specifically binding polypeptides and metal complexes are claimed. These compounds are also to bind to plaque and thus make possible their diagnosis and therapy. As diagnostic methods, scintigraphy, computer tomography, and MRI are mentioned. While scintigraphy is confirmed by experiment, data is lacking for MRI.
Labeled phycocyanines are claimed as contrast media for the imaging of plaque in U.S. Pat. No. 5,807,536. As diagnostic methods, radiography, computer tomography, scintigraphy, SPECT and MRI are mentioned here. Scintigraphy is confirmed by experiment.
Numerous contrast media for infarction and necrosis imaging are known from the literature. Tests were carried out early on to improve the localization of infarctions and necroses by use of contrast media in noninvasive processes such as scintigraphy or nuclear spin tomography. The literature devotes a great deal of space to attempts to use porphyrins for necrosis imaging. The results that are achieved paint a contradictory picture, however. Winkelman and Hoyes thus describe in Nature, 200, 903 (1967) that manganese-5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrin (TPPS) selectively accumulates in the necrotic portion of a tumor.
Lyon et al. (Magn. Res. Med. 4, 24 (1987)) observed, however, that manganese-TPPS is dispersed into the body, specifically into the kidney, liver, tumor and only in a small portion to the muscles. It is advantageous in this case that the concentration in the tumor reach its maximum only on the fourth day and also only after the authors have increased the dose from 0.12 mmol/kg to 0.2 mmol/kg. The authors therefore also speak of a non-specific uptake of TPPS in the tumor. Bockhurst et al. in turn report in Acta Neurochir 60, 347 (1994, Suppl.) that MnTPPS binds selectively to tumor cells.
Foster et al. (J. Nucl. Med. 26, 756 (1985)) in turn found that 111In-5,10,15,20-tetrakis-(4-N-methyl-pyridinium)-porphyrin (TMPyP) does not accumulate in the necrotic portion, but rather in the living edge areas. It follows from the above that a porphyrin-tissue interaction exists, is obvious but not necessary.
In Circulation Vol. 90, No. 4, part 2, page 1468, Abstract No. 2512 (1994), Ni et al. report that they can visualize infarction areas with a manganese-tetraphenyl-porphyrin (Mn-TPP) and a gadolinium-mesoporphyrin (Gd-MP). In International Patent Application WO 95/31219, both substances were used for infarction and necrosis imaging. The authors Marchal and Ni write (see Example 3) that for the compound Gd-MP, the metal content of the infarcted kidney was as high as that of the non-infarcted organ, but that for the myocardium in the infarcted tissue (Example 1), it was nine times as high. It was surprising that the ratio of the signal intensities during MRI for infarcted tissue in comparison to healthy tissue was comparatively high in both cases, at 2.10 or 2.19. Other metalloporphyrins were described in Application DE 19835082 (Schering AG).
Porphyrins tend to be stored in the skin, which results in photosensitization. The sensitization can last for days, and indeed even weeks. This is an undesirable side effect when using porphyrins as diagnostic agents. In addition, the therapeutic index for porphyrins is only very small, since, e.g., for Mn-TPPS, an action starts only at a dose of 0.2 mmol/kg, but the LD50 is already approximately 0.5 mmol/kg.
Contrast media for necrosis and infarction imaging not derived from the porphyrin skeleton have been described in DE 19744003 (Schering AG), DE 19744004 (Schering AG) and WO 99/17809 (EPIX).
In DE 19744003, oligomeric compounds, which consist of a nucleus and are bonded to the 1-3 metal complexes, are claimed.
In Application 19744004, lipophilic metal complexes for necrosis and infarction imaging are claimed. These compounds include metal complexes of polyaminopolycarboxylic acids, polyaminopolyphosphonic acids, porphyrins, texaphyrins, sapphyrins, and peptides.
In EPIX-Application WO 99/17809, the use of DTPA derivatives for necrosis imaging is claimed. The most prominent compound is the gadolinium complex of a phosphodiester of hydroxymethyl-DTPA (MS-325).
Perfluoroalkyl-containing metal complexes are also known as contrast media for MR-imaging. WO 97/26017 (Schering) and WO 99/01161 (Schering) thus disclose the use of perfluoroalkyl-containing metal complexes as lymphographic agents. In addition, WO 99/01161 also describes the suitability of these compounds for visualizing the vascular space (blood-pool agents).
Contrast media were also described for the individual visualization of tumors and necroses using MR-imaging.
In EP 417870 A1, compounds for tumor diagnosis and therapy are disclosed. It is stated that infarctions and ischemias can also be visualized. An experimental confirmation of this information cannot be derived from the application, however. The claimed compounds are chelates of complexes of N2S2 and N3S types with radioisotopes. Scintigraphy is used as a diagnostic method.
In DE 19646762, scintigraphy is also used as a diagnostic method. In the publication, metal chelates are claimed as radiosensitizers for therapy of hypoxic tumors and for diagnosis of hypoxic conditions and necroses. In the descriptive part, NMR-diagnosis, x-ray diagnosis and radiodiagnosis are mentioned as diagnostic processes.
In German Application DE 19824653, porphyrins are claimed as necrosis-affine substances for the therapy of tumors. In the application, it is explained that the compounds are concentrated in the necrotic and hypoxic areas of the tumors. The compounds can be used for diagnostic purposes in the form of their metal derivatives with paramagnetic ions or radioisotopes.
It is common to both applicationsxe2x80x94DE 19646762 and DE 19824653xe2x80x94that the visualization of necroses and tumors does not take place independently of one another, but rather that the necrosis is part of the tumor.
The object of this invention was to make available contrast media for MR-imaging, which are suitable both for visualization of plaque, lymph nodes, infarcted and necrotic tissue and for independent visualization of necroses and tumors.
Surprisingly enough, it was now found that perfluoroalkyl-containing metal complexes, which have a critical micelle formation concentration of  less than 10xe2x88x923 mol/l, a hydrodynamic micelle diameter (2 Rh) greater than 1 nm and a proton relaxivity in plasma (R1) greater than 10 l/mmolxc2x7s, are very well suited as contrast media in MR imaging for visualization of plaque. In addition, these compounds can be used both for visualization of lymph nodes, infarcted and necrotic tissue and for independent visualization of necrotic tissue and tumor tissue.
Amphiphilic compounds, which have a perfluoroalkyl side chain in the molecule as a nonpolar portion that is optionally connected to the total molecule via a lipophilic linker, are defined as perfluoroalkyl-containing metal complexes that are suitable for use according to the invention. The polar portion of the compounds according to the invention is formed by one or more metal complexes and optionally other existing polar groups.
In aqueous systems, these amphiphilic molecules show the properties that are characteristic of standard surfactants (such as, e.g., sodium dodecylsulfate, SDS). They thus reduce the surface tension of water. By tensiometry, the so-called CMC (critical micelle formation concentration in mol/l) can be determined. In this respect, the surface tension is determined based on the concentration of the substance to be measured. The CMC can be calculated from the plot of the surface tension function (c) that is obtained. The critical micelle formation concentration of the compounds according to the invention must be  less than 10xe2x88x923 mol/l, preferably  less than 10xe2x88x924 mol/l.
The amphiphilic compounds according to the invention are combined in solution and are present as aggregates. The size (2 Rh) of such aggregates (e.g., micelles, rods, wafers, etc.) can be determined with the aid of photon-correction spectroscopy (PCS).
As a second criterion, the hydrodynamic micelle diameter 2 Rh, which must be  greater than 1 nm, is therefore used. Those perfluoroalkyl-containing metal complexes according to the invention whose 2 RH is xe2x89xa73, quite especially preferably  greater than 4 nm, are especially suitable.
Both the determination of the CMC and the photon correlation spectroscopy are described in H.-D. Dxc3x6rfler, xe2x80x9cGrenzflxc3xa4chen- und Kolloidchemie [Interface and Colloid Chemistry],xe2x80x9d Weinheim, New York, Basel, Cambridge, Tokyo, VSH 1994.
As a third criterion, the proton-relaxivity in plasma (R1) at 40xc2x0 C. and a field strength of 0.47 tesla is used. The relaxivity, which is indicated in [l/mmolxc2x7s], is the quantitative measurement for the shortening of relaxation time T1 of the protons. For the purpose according to the invention, the relaxivity must be as high as possible and  greater than 10 l/mmolxc2x7s, preferably  greater than 13 l/mmolxc2x7s, especially preferably  greater than 15 l/mmolxc2x7s.
Relaxivity R1 [l/mmolxc2x7s] of the MR-contrast media according to the invention was determined with the Minispec P 20 device of the Bruker Company. The measurements were taken at 40xc2x0 C. and a field strength of 0.47 tesla. Eight measuring points were recorded by each T1-sequence: 180xc2x0-TI-90xc2x0, inversion recovery. As a medium, bovine plasma of the Kraeber Company was used. The contrast medium concentrations [mmol/l] in the batches were between 0.30 and 1.16.
In an embodiment of this invention, the compounds of general formula I according to claims 8 to 11 are used as preferred compounds. In this case, these are known compounds that are described in WO 97/26017. Their production can also be found in this WO publication. Surprisingly enough, it has been shown that these compounds are also very well suited as MRI-contrast media for visualization of plaque. As quite especially preferred compounds, metal complexes I-IV, VI and XI-XIII (cf. also Table 1) are used.
In another embodiment of this invention, those compounds of general formula Ia according to claims 12 to 21 are used as preferred compounds. These compounds are known and are described in WO 99/01161. Their use as MRI contrast media for visualization of plaque still had not been described to date. Of these compounds, quite especially preferably metal complex XIV (cf. Table 1) is used.
The present invention includes a method for MRI imaging comprising administering to a patient an MRI contrast agent, comprising a perfluoroalkyl-containing metal complex that has a critical micelle formation concentration  less than 10xe2x88x923 mol/l, a hydrodynamic micelle diameter (2 Rh) greater than 1 nm and a proton relaxivity in plasma (R1) greater than 10 l/mmolxc2x7s and conducting MRI imaging whereby plaque, or necrotic tissue are visualized or necroses and tumors are independently visualized.
In an embodiment the metal complex has a micelle formation concentration of  less than 10xe2x88x924 mol/l.
In an embodiment the metal complex has a hydrodynamic micelle diameter of  greater than 3 nm.
In an embodiment the metal complex has a proton relaxivity in plasma of  greater than 13 l/mmolxc2x7s.
In an embodiment the perfluoroalkyl-containing metal complex is a compound of formula I
RFxe2x80x94Lxe2x80x94Kxe2x80x83xe2x80x83I
in which
RF is a perfluorinated, straight-chain or branched carbon chain with formula xe2x80x94CnF2nE, in which
E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n is a number from 4-30,
L is a direct bond, a methylene group, an xe2x80x94NHCOxe2x80x94 group, a group 
whereby p is a number from 0 to 10, and q and n, independently of one another, are 0 or 1, and Ra is a hydrogen atom, a methyl group, a xe2x80x94CH2xe2x80x94OH group, a xe2x80x94CH2xe2x80x94CO2H group or a C2-C15 alkyl, which optionally is interrupted by 1 to 3 oxygen atoms, 1 to 2 CO groups or an optionally substituted aryl group and/or is substituted with 1 to 4 hydroxyl groups, 1 to 2 C1-C4 alkoxy groups, 1 to 2 carboxy groups, or a group xe2x80x94SO3H,
or
L is a straight-chain, branched, saturated or unsaturated C2-C30 carbon chain, which optionally contains 1 to 10 oxygen atoms, 1 to 3 xe2x80x94NRa groups, 1 to 2 sulfur atoms, a piperazine group, a xe2x80x94CONRa group, an xe2x80x94NRaCO group, an xe2x80x94SO2 group, an xe2x80x94NRaxe2x80x94CO2 group, 1 to 2 CO groups, a group xe2x80x94COxe2x80x94Nxe2x80x94Txe2x80x94N(Ra)xe2x80x94SO2xe2x80x94RF, or 1 to 2 optionally substituted aryls and/or is interrupted by these groups and/or is optionally substituted with 1 to 3 xe2x80x94ORa groups, 1 to 2 oxo groups, 1 to 2 xe2x80x94NHxe2x80x94CORa groups, 1 to 2 xe2x80x94CONHRa groups, 1 to 2 xe2x80x94(CH2)pxe2x80x94CO2H groups, 1 to 2 groups xe2x80x94(CH2)pxe2x80x94(O)qxe2x80x94CH2CH2xe2x80x94RF,
whereby
Ra, RF and p and q have the above-indicated meanings, and
T is a C2-C10 chain, which optionally is interrupted by 1 to 2 oxygen atoms or 1 to 2 xe2x80x94NHCO groups,
K is a complexing agent or metal complex of formula II 
xe2x80x83in which Rc, R1 and B are independent of one another, and
Rc is Ra or is xe2x80x94(CH2)m-Lxe2x80x94RF, whereby m is 0, 1 or 2, and L and RF have the above-mentioned meaning,
R1, independently of one another, is a hydrogen atom or a metal ion equivalent of atomic numbers 22-29, 42-46 or 58-70,
B is xe2x80x94OR1, 
whereby R1, L, RF and Rc have the above-mentioned meanings, or
K is a complexing agent or complex of formula III 
in which Rc and R1 have the above-mentioned meanings and Rb has the meaning of Ra 
or
K is a complexing agent or complex of formula IV 
in which R1 has the above-mentioned meaning
or
K is a complexing agent or complex of formula V 
in which R1 has the above-mentioned meaning, and o and q stand for numbers 0 or 1, and yields the sum o+q=1,
or
K is a complexing agent or complex of formula VI 
in which R1 has the above-mentioned meaning or
K is a complexing agent or complex of formula VII 
in which R1 and B have the above-mentioned meanings
or
K is a complexing agent or complex of formula VIII 
in which Rc and R1 have the above-mentioned meanings, and Rb is Ra 
or
K is a complexing agent or complex of formula IX 
in which Rc and R1 have the above-mentioned meanings,
or
K is a complexing agent or complex of formula X 
in which Rc and R1 have the above-mentioned meanings,
or
K is a complexing agent or complex of formula XI 
in which R1, p and q have the above-mentioned meanings,
and Rb has the meaning of Ra,
or
K is a complexing agent or complex of formula XII 
in which L, RF and Z1 have the above-mentioned meanings,
or
K is a complexing agent or complex of formula XIII 
in which R1 has the above-mentioned meaning, or
K is a salt of one of the complexing agents or complexes of fomula II to XIII with an organic and/or inorganic base or amino acid or amino acid amide.
In an embodiment the compound of formula I, is a compound in which
L is
xcex1-CH2-xcex2
xcex1-CH2CH2-xcex2
xcex1-(CH2)s-xcex2 s=3-15
xcex1-CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2xe2x80x94)t-xcex2 t=2-6
xcex1-CH2xe2x80x94NHxe2x80x94CO-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(CH2COOH)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C10H21)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C6H13)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94(CH2)10xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94C6H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94CH2xe2x80x94OH)SO2-xcex2
xcex1-CH2xe2x80x94NHCOxe2x80x94(CH2)10xe2x80x94Sxe2x80x94CH2CH2-xcex2
xcex1-CH2NHCOCH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2NHCO(CH2)10xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94C(CH2xe2x80x94OCH2CH2xe2x80x94C6F13)2xe2x80x94CH2xe2x80x94OCH2xe2x80x94CH2-xcex2
xcex1-CH2xe2x80x94NHCOCH2CH2CONxe2x80x94CH2CH2NHCOCH2N(C2H5)SO2C8F17CH2xe2x80x94CH2NHCOCH2N(C2H5)xe2x80x94SO2-xcex2
xcex1-CH2Oxe2x80x94CH2xe2x80x94CH(OC10H21)xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-(CH2NHCO)4xe2x80x94CH2Oxe2x80x94CH2CH2-xcex2
xcex1-(CH2NHCO)3xe2x80x94CH2Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94OCH2C(CH2OH)2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2NHCOCH2N(C6H5)xe2x80x94SO2-xcex2
xcex1-NHCOxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-NHCOxe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-NHxe2x80x94CO-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(CH2COOH)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C10H21)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C6H13)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94(CH2)10xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2-C6H5)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94CH2xe2x80x94OH)SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2-xcex2
xcex1-CH2xe2x80x94Oxe2x80x94C6H4xe2x80x94Oxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-CH2xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-N(C2H5)xe2x80x94SO2-xcex2
xcex1-N(C6H5)xe2x80x94SO2-xcex2
xcex1-N(C10H21)xe2x80x94SO2-xcex2
xcex1-N(C6H13)xe2x80x94SO2-xcex2
xcex1-N(C2H4OH)xe2x80x94SO2-xcex2
xcex1-N(CH2COOH)xe2x80x94SO2-xcex2
xcex1-N(CH2C6H5)xe2x80x94SO2-xcex2
xcex1-N-[CH(CH2OH)2]xe2x80x94SO2-xcex2or
xcex1-N-[CH(CH2OH)CH(CH2OH)]xe2x80x94SO2-xcex2,
in which xcex1 is the binding site to the complexing agent or metal complex K, and xcex2 is the binding site to the fluorine radical.
In an embodiment the compound of formula I, is a compound in which n in formula xe2x80x94CnF2nE is a number from 4-15 and/or E is a fluorine atom.
Also preferred are the following compounds of formula I:
Gadolinium complex of 10-[1-methyl-2-oxo-3-aza-5-oxo-{4-perfluorooctylsulfonyl-piperazin-1-yl}-pentyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17-heptadecafluoroheptadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
Gadolinium complex of 10-[2-hydroxy-4-aza-5,9-dioxo-9-{4-perfluorooctyl)-piperazin-1-yl}-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
Gadolinium complex of 10-[2-hydroxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorotetradecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,xe2x88x9216,16,17,17,18,18,19,19-henicosafluorononadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-11-aza-11-(perfluorooctylsulfonyl)-tridecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, or
Gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-8-phenyl-octyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraaza-cyclododecane.
In an embodiment the perfluoroalkyl-containing metal complex, is a compound of formula Ia
Axe2x80x94RFxe2x80x83xe2x80x83(Ia)
in which
A is a group that contains 2 to 6 metal complexes, which are bonded directly or via a linker to a nitrogen atom of an annular skeleton chain, and
RF is a perfluorinated, straight-chain or branched carbon chain with formula xe2x80x94CnF2nE, in which
E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n is a number from 4-30,
whereby A has the following structure: 
whereby
q1 is 0, 1, 2 or 3,
K is a complexing agent or metal complex or a salts thereof with an organic and/or inorganic base or amino acid or amino acid amide,
X as the point of attachment to RF, is a direct bond, a phenylene group or a C1-C10 alkylene chain, which optionally contains 1-15 oxygen atoms, 1-5 sulfur atoms, 1-10 carbonyl groups, 10xe2x80x9410 (NRd) groups, 1-2 NRdSO2 groups, 1-10 CONRd groups, 1 piperidine group, 1-3 SO2 groups and/or 1-2 phenylene groups or optionally is substituted by 1-3 radicals RF, in which Rd is a hydrogen atom, a phenyl group, benzyl group or a C1-C15 alkyl group, which optionally contains 1-2 NHCO, 1-2 CO groups, 1-5 oxygen atoms and optionally is substituted by 1-5 hydroxy, 1-5 methoxy, 1-3 carboxy, or 1-3 RF radicals,
V is a direct bond or a chain of formula IIa or IIIa: 
xe2x80x83in which
Re is a hydrogen atom, a phenyl group, a benzyl group or a C1-C7 alkyl group, which optionally is substituted with a carboxy group, a methoxy group or a hydroxy group,
W is a direct bond, a polyglycol ether group with up to 5 glycol units, or a group of formula IVa
xe2x80x94CH(Rh)xe2x80x94xe2x80x83xe2x80x83(IVa)
xe2x80x83in which Rh is a C1-C7 carboxylic acid, a phenyl group, a benzyl group or a xe2x80x94(CH2)1-5xe2x80x94NHxe2x80x94K group,
xcex1 is the binding to the nitrogen atom of the skeleton chain, xcex2 is the binding to complexing agent or metal complex K,
and in which variables k and m stand for natural numbers between 0 and 10, and I is 0 or 1
xe2x80x83and whereby
D is a CO or SO2 group.
Also preferred are compounds of formula Ia in which q1 is the number 1.
In an embodiment the compound of formula Ia is a compound in which X is an alkylene chain, which contains 1-10 xe2x80x94CH2CH2Oxe2x80x94 groups or 1-5 xe2x80x94COCH2NHxe2x80x94 groups, a direct bond or one of the following structures 
whereby
xcex3 binds to D, and xcex4 binds to RF.
In an embodiment the compound of formula Ia, is a compound in which V is a group with one of the following structures 
In an embodiment the compound of formula Ia, is a compound in which K is a complexing agent or complex of formula Va, VIa, VIIa or VIIIa, 
whereby
R1, independently of one another, are a hydrogen atom or a metal ion equivalent of the elements of atomic numbers 23-29, 42-46 or 58-70,
R8 is a hydrogen atom or a straight-chain, branched, saturated or unsaturated C1-C30 alkyl chain, which optionally is substituted by 1-5 hydroxy, 1-3 carboxy or 1 phenyl group(s) and/or optionally is interrupted by 1-10 oxygen atoms, 1 phenylene group or 1 phenylenoxy group,
R6 are independently a hydrogen atom, a straight-chain or branched C1-C7 alkyl radical, a phenyl radical or benzyl radical,
R7 is a hydrogen atom, a methyl group or ethyl group, which optionally is substituted by a hydroxy group or carboxy group,
U3 is a straight-chain, branched, saturated or unsaturated C1-C20 alkylene group optionally containing 1-5 imino groups, 1-3 phenylene groups, 1-3 phenylenoxy groups, 1-3 phenylenimino groups, 1-5 amide groups, 1-2 hydrazide groups, 1-5 carbonyl groups, 1-5 ethylenoxy groups, 1 urea group, 1 thiourea group, 1-2 carboxyalkylimino groups, 1-2 ester groups, 1-1-0 oxygen atoms, 1-5 sulfur atoms and/or 1-5 nitrogen atoms, and/or optionally substituted by 1-5 hydroxy groups, 1-2 mercapto groups, 1-5 oxo groups, 1-5 thioxo groups, 1-3 carboxy groups, 1-5 carboxyalkyl groups, 1-5 ester groups and/or 1-3 amino groups, whereby the optionally contained phenylene groups can be substituted by 1-2 carboxy groups, 1-2 sulfone groups or 1-2 hydroxy groups
T1 is a xe2x80x94CO-xcex2, xe2x80x94NHCO-xcex2 or xe2x80x94NHCS-xcex2 group, whereby xcex2 is the binding site to V.
In an embodiment the compound of formula Ia is a C1-C20 alkylene chain that is U3 contains the group xe2x80x94CH2NHCOxe2x80x94, xe2x80x94NHCOCH2Oxe2x80x94, xe2x80x94NHCOCH2OC6H4xe2x80x94, xe2x80x94N(CH2CO2H)xe2x80x94, xe2x80x94CH2OCH2xe2x80x94, xe2x80x94NHCOCH2C6H4xe2x80x94, xe2x80x94NHCSNHC6H4xe2x80x94, xe2x80x94CH2OC6H4xe2x80x94, or xe2x80x94CH2CH2Oxe2x80x94 and/or is substituted by the group xe2x80x94COOH and/or xe2x80x94CH2COOH.
In an embodiment the compound of formula Ia, U3 is a xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94C6H4xe2x80x94, xe2x80x94C6H10xe2x80x94, xe2x80x94CH2C6H4xe2x80x94, xe2x80x94CH2NHCOCH2CH(CH2CO2 H)xe2x80x94C6H4xe2x80x94, xe2x80x94CH2NHCOCH2OCH2xe2x80x94, or xe2x80x94CH2NHCOCH2C6H4xe2x80x94 group,
In an embodiment the compound of formula Ia, is a compound in which K has one of the following structures: 
In an embodiment the compound of formula Ia is a compound in which the perfluoroalkyl chain is RF is xe2x80x94C6F13, xe2x80x94C8F17, xe2x80x94C10F21 or xe2x80x94C12F25.
In an embodiment the compound of formula Ia is 1,4,7-tris{1,4,7-tris(N-(carboxylatomethyl)-10-[N-1-methyl-3,6-diaza-2,5,8-trioxooctane-1,8-diyl)]-1,4,7,10-tetraazacyclododecane, Gd complex}-10-[N-2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoyl]-1,4,7,10-tetraazacyclododecane .
In an embodiment the metal complex has a hydrodynamic micelle diameter of  greater than 4 nm.
In an embodiment the metal complex has a proton relaxivity in plasma of  greater than 15 l/mmolxc2x7s.
In an embodiment the perfluoroalkyl-containing metal complex is in a galenical formulation that contains a paramagnetic, perfluoroalkyl-containing metal complex of formula Ia and diamagnetic perfluoroalkyl-containing substance, optionally dissolved in an aqueous solvent.
In an embodiment the perfluoroalkyl-containing metal complex is in a galenical formulations that contains a paramagnetic, perfluoroalkyl-containing metal complex of formula Ib, and a diamagnetic perfluoroalkyl-containing substance, optionally dissolved in an aqueous solvent.
In another preferred embodiment of the invention, the macrocyclic perfluoroalkyl compounds of general formula Ib 
in which
K means a complexing agent or a metal complex of general formula IIb 
whereby
R1 stands for a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70,
R2 and R3 stand for a hydrogen atom, a C1-C7 alkyl group, a benzyl group, a phenyl group, xe2x80x94CH2OH or xe2x80x94CH2xe2x80x94OCH3, and
U2 stands for radical L1, whereby L1 and U2, independently of one another, can be the same or different,
A1 means a hydrogen atom, a straight-chain or branched C1-C30-alkyl group, which optionally is interrupted by 1-15 oxygen atoms, and/or optionally is substituted with 1-10 hydroxy groups, 1-2 COOH groups, a phenyl group, a benzyl group and/or 1-5 xe2x80x94OR9 groups, with R9 in the meaning of a hydrogen atom or a C1-C7-alkyl radical, or xe2x80x94L1xe2x80x94RF,
L1 means a straight-chain or branched C1-C30-alkylene group, which optionally is interrupted by 1-10 oxygen atoms, 1-5 xe2x80x94NHxe2x80x94CO groups, 1-5 xe2x80x94COxe2x80x94NH groups, by a phenylene group optionally substituted by a COOH group, 1-3 sulfur atoms, 1-2 xe2x80x94N(B1)xe2x80x94SO2 groups and/or 1-2 xe2x80x94SO2xe2x80x94N(B1) groups with B1 in the meaning of A1, an NHCO group, a CONH group, an N(B1)xe2x80x94SO2 group or an xe2x80x94SO2xe2x80x94N(B1) group and/or optionally is substituted with radical RF, and
RF means a straight-chain or branched perfluorinated alkyl radical of formula CnF2nE, whereby n stands for numbers 4-30, and
E stands for a terminal fluorine atom, chlorine atom, bromine atom, iodine atom or a hydrogen atom,
and optionally present acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides, can be used.
Since the compounds according to the invention are intended for use in NMR diagnosis, the metal ion of the signaling group must be paramagnetic. These are in particular the divalent and trivalent ions of the elements of atomic numbers 23-29, 42-46 and 58-70. Suitable ions are, for example, the chromium(III), iron(II), cobalt(II), nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(III) and ytterbium(III) ions. Because of their strong magnetic moments, gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), iron(III) and manganese(II) ions are especially preferred.
Preferred are manganese(II), iron(II), iron(III), praseodymium(III), neodymium(III), samarium(III), gadolinium(III) and ytterbium(III) ions, especially dysprosium(III) ions.
Alkyl groups R2, R3, and R9 can be straight-chain or branched. By way of example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, and 1,2-dimethylpropyl can be mentioned.
Hydrogen and C1-C4 alkyl groups are preferred for R2, R3 and R9; hydrogen and the methyl group are especially preferred.
The benzyl group and phenyl group R2, A1 and B1 can be substituted in the phenyl ring. The COOH group is suitable as a substituent.
If the compound of formula Ib contains radicals L1 and U2 at the same time, L1 and U2 can be different from one another.
C1-C30 alkylene groups U2 can be straight-chain or branched. By way of example, methylene, ethylene, propylene, isopropylene, n-butylene, 1-methylpropylene, 2-methylpropylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, and 1,2-dimethylpropylene can be mentioned.
For U2 in the meaning of alkylene, C1-C10 alkylene groups are preferred; C1-C4 alkylene groups are especially preferred.
C1-C30 alkyl groups A1 can be straight-chain or branched. By way of example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, and n-hexyl can be mentioned.
C1-C30 alkyl groups A1 can be interrupted by 1-15 oxygen atoms and/or substituted with 1-10 hydroxy groups, 1-5 alkoxy groups or 1-2 COOH groups, such as, e.g.,
C2H4xe2x80x94Oxe2x80x94CH3, C3H6xe2x80x94Oxe2x80x94CH3,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)txe2x80x94C2H4xe2x80x94OH, C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)txe2x80x94C2H4xe2x80x94OCH3 with t=0 to 13
C2H4OH, C3H6OH, C4H8OH, C5H10OH, C6H12OH, C7H14OH, as well as their branched isomers,
CH(OH)CH2OH,
CH(OH)CH(OH)CH2OH, CH2[CH(OH)]u1CH2OH, with u1=1-10
CH[CH2(OH)]CH(OH)CH2OH,
C2H4CH(OH)CH2OH,
(CH2)sCOOH with s=1 to 15,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)txe2x80x94CH2COOH with t=0 to 13,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)txe2x80x94C2H4xe2x80x94CnF2nE with t=0 to 13, n=4 to 20 and
E=a fluorine, hydrogen, chlorine, bromine or iodine atom.
Preferred meanings of A1 are hydrogen, C1-C10-alkyl,
C2H4xe2x80x94Oxe2x80x94CH3, C3H6xe2x80x94Oxe2x80x94CH3,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)xxe2x80x94C2H4xe2x80x94OH, C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)xxe2x80x94C2H4xe2x80x94OCH3 with x=0 to 5,
C2H4OH, C3H6OH,
CH2[CH(OH)]yCH2OH, with y=1-6
CH[CH2(OH)]CH(OH)CH2OH,
(CH2)wCOOH with w=1 to 10,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)xxe2x80x94CH2COOH with x=0 to 5,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)xxe2x80x94C2H4xe2x80x94CnF2nE with x=0 to 5, n=4 to 15, and
E=a fluorine atom.
If the compound of general formula Ib contains two radicals L1xe2x80x94RF, these radicals can be different from one another.
For radicals L1, there can be mentioned by way of example, whereby a stands for the binding to the nitrogen atom and xcex2 stands for the binding to radical RF:
xcex1-(CH2)s-xcex2 with s=1-15
xcex1-CH2xe2x80x94CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2xe2x80x94)y-xcex2 with y=1-6
xcex1-CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2xe2x80x94)y-xcex2 with y=1-6
xcex1-CH2xe2x80x94NHxe2x80x94CO-xcex2
xcex1-CH2xe2x80x94CH2xe2x80x94NHxe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(CH2COOH)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C10H21)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C6H13)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94(CH2)10xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94C6H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94CH2xe2x80x94OH)SO2-xcex2
xcex1-CH2xe2x80x94NHCOxe2x80x94(CH2)10xe2x80x94Sxe2x80x94CH2CH2-xcex2
xcex1-CH2NHCOCH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94CH2NHCOCH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94(CH2xe2x80x94CH2xe2x80x94O)yxe2x80x94(CH2)3NHCOxe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2 with y=1-6
xcex1-CH2NHCO(CH2)10xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2CH2NHCO(CH2)10xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2CH2-xcex2, whereby the phenylene group 1,4 or 1,3 is linked
xcex1-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94C(CH2xe2x80x94OCH2CH2xe2x80x94C6F13)2xe2x80x94CH2xe2x80x94OCH2xe2x80x94CH2-xcex2
xcex1-CH2xe2x80x94NHCOCH2CH2CONxe2x80x94CH2CH2NHCOCH2N(C2H5)SO2C8F17xcex2
xcex1-CH2xe2x80x94CH2NHCOCH2N(C2H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH(OC10H21)xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2NHCO)4xe2x80x94CH2Oxe2x80x94CH2CH2-xcex2
xcex1-(CH2NHCO)3xe2x80x94CH2Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94OCH2C(CH2OH)2xe2x80x94CH213 Oxe2x80x94CH2CH2-xcex2
xcex1-CH2NHCOCH2N(C6H5)xe2x80x94SO2-xcex2
xcex1-NHCOxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-NHCOxe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-NHxe2x80x94CO-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(CH2COOH)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C10H21)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C6H13)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94(CH2)10xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94C6H5)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94CH2xe2x80x94OH)SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2-xcex2
xcex1-CH2xe2x80x94Oxe2x80x94C6H4xe2x80x94Oxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-CH2xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-N(C2H5)xe2x80x94SO2-xcex2
xcex1-N(C6H5)xe2x80x94SO2-xcex2
xcex1-N(C10H21)xe2x80x94SO2-xcex2
xcex1-N(C6H13)xe2x80x94SO2-xcex2
xcex1-N(C2H4OH)xe2x80x94SO2-xcex2
xcex1-N(CH2COOH)xe2x80x94SO2-xcex2
xcex1-N(CH2C6H5)xe2x80x94SO2-xcex2
xcex1-Nxe2x80x94[CH(CH2OH)2]xe2x80x94SO2-xcex2
xcex1-Nxe2x80x94[CH(CH2OH)CH(OH)(CH2OH)]xe2x80x94SO2-xcex2
Preferred are:
xcex1-CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2xe2x80x94)y-xcex2 with y=1-6
xcex1-CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2xe2x80x94)y-xcex2 with y=1-6
xcex1-CH2xe2x80x94CH2xe2x80x94NHxe2x80x94SO2-xcex2 Example 10
xcex1-CH2NHCOCH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94CH2NHCOCH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94(CH2xe2x80x94CH2xe2x80x94O)yxe2x80x94(CH2)3NHCOxe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2 with y=1-6
xcex1-CH2NHCO(CH2)10xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2CH2NHCO(CH2)10xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH(OC10H21)xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94Oxe2x80x94C6H4xe2x80x94Oxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-CH2xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2xe2x80x94CH2-xcex2
According to the invention, radicals L1 of the compounds mentioned in the examples of the description of this invention are quite especially preferred.
U2 is considered to stand for the above-cited radicals for L1 and the radicals that are characterized as preferred and especially preferred, and the above-cited and optionally preferred and especially preferred radicals are considered to stand for the meaning of alkylene, provided that no xcex1-position nitrogen atom and no terminal (xcex2-position) SO2 or CO group must be present.
Preferred radicals B1 are hydrogen, straight-chain or branched C1-C10-alkyl radicals, which optionally are interrupted by 1-5 oxygen atoms and/or optionally are substituted with 1-5 hydroxy groups, 1-2 COOH groups, a phenyl group optionally substituted by a COOH group, a benzyl group and/or 1-5 OR9 groups, with R9 in the meaning of a hydrogen atom or a C1-C3 alkyl radical.
Preferred radicals RF are straight-chain or branched perfluorinated alkyl radicals of formula CnF2nE, whereby n stands for numbers 4 to 15 and E stands for a terminal fluorine atom.
The production of the compounds of general formula Ib according to the invention 
with
K in the meaning of a complexing agent or a metal complex of general formula IIb 
can be carried out according to the following process:
Process A.
The carboxylic acid of Formula IIIb already contains metal ion equivalent R1. 
Carboxylic acid IIIb that is optionally activated in situ with R1 in the meaning of a metal ion equivalent is reacted with an amine IVb in a coupling reaction to form an amide Ib.
This process for the production of metal complex carboxylic acid amides is known from DE 196 52 386.
The mixture of metal complex carboxylic acid IIIb that is used in the coupling reaction and that contains optionally present carboxy and/or hydroxy groups in protected form and at least one solubilizing substance in an amount up to 5, preferably 0.5-2 molar equivalents relative to the metal complex carboxylic acid, can both be produced in an upstream reaction stage and isolated (e.g., by concentration by evaporation, freeze-drying or spray-drying of an aqueous or water-miscible solution of components or by precipitation with an organic solvent from such a solution) and then can be reacted in DMSO with dehydrating reagent and optionally a coupling adjuvant and can be formed in situ optionally by the addition of solubilizing substance(s) for DMSO-suspension of metal complex carboxylic acid, dehydrating reagent and optionally a coupling adjuvant.
The reaction solution that is produced according to one of these processes is kept for pretreatment (acid activation) for 1 to 24 hours, preferably 3 to 12 hours at temperatures of 0 to 50xc2x0 C., preferably at room temperature.
Then, an amine of general formula IVb 
in which radicals R3, L1, RF and A have the above-indicated meanings, is added without solvent or dissolved in, for example, dimethyl sulfoxide, alcohols, such as, e.g., methanol, ethanol, isopropanol or mixtures thereof, formamide, dimethylformamide, water or mixtures of the cited solvents, preferably in dimethyl sulfoxide, in water or in solvents that are mixed with water. For amide coupling, the thus obtained reaction solution is kept at temperatures of 0 to 70xc2x0 C., preferably 30 to 60xc2x0 C., for 1 to 48 hours, preferably 8 to 24 hours.
In some cases, it has proven advantageous to use the amine in the form of its salts, e.g., as hydrobromide or hydrochloride, in the reaction. To release the amine, a base such as, e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, tripropylamine, tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate is added.
The optionally still present protective groups are then cleaved off.
The isolation of the reaction product is carried out according to the methods that are known to one skilled in the art, preferably by precipitation with organic solvents, preferably acetone, 2-butanone, diethyl ether, ethyl acetate, methyl-t-butylether, isopropanol or mixtures thereof. Further purification can be carried out by, for example, chromatography, crystallization or ultrafiltration.
As solubilizing substances, alkali salts, alkaline-earth salts, trialkylammonium salts, tetraalkylammonium salts, ureas, N-hydroxyimides, hydroxyaryltriazoles, substituted phenols and salts of heterocyclic amines are suitable. By way of example, there can be mentioned: lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, lithium methanesulfonate, sodium methanesulfonate, lithium-p-toluenesulfonate, sodium-p-toluenesulfonate, potassium bromide, potassium iodide, sodium chloride, magnesium bromide, magnesium chloride, magnesium iodide, tetraethylammonium-p-toluenesulfonate, tetramethylammonium-p-toluenesulfonate, pyridinium-p-toluenesulfonate, triethylammonium-p-toluenesulfonate, 2-morpholinoethylsulfonic acid, 4-nitrophenol, 3,5-dinitrophenol, 2,4-dichlorophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, urea, tetramethylurea, N-methylpyrrolidone, formamide, as well as cyclic ureas, whereby the five first-mentioned are preferred.
As dehydrating reagents, all agents that are known to one skilled in the art are used. By way of example, carbodiimides and onium reagents, such as, e.g., dicyclohexylcarbodiimide (DCCI), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-hydroxychloride (EDC), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP) and O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU), preferably DCCI, can be mentioned.
In the literature, for example, the following suitable processes are described:
Aktivierung von Carbonsxc3xa4uren. xc3x9cbersicht in Houben-Weyl, Methoden der Organischen Chemie [Activation of Carboxylic Acids. Survey in Houben-Weyl, Methods of Organic Chemistry], Volume XV/2, Georg Thieme Verlag Stuttgart, 1974 (and J. Chem. Research (S) 1996, 302).
Aktivierung mit Carbodiimiden [Activation with Carbodiimides]. R. Schwyzer and H. Kappeler, Helv. 46: 1550 (1963).
E. Wxc3xcnsch et al., Vol. 100: 173 (1967).
Aktivierung mit Carbodiimiden/Hydroxysuccinimid [Activation with Carbodiimides/Hydroxysuccinimide]: J. Am. Chem. Soc. 86: 1839 (1964) and J. Org. Chem. 53: 3583 (1988). Synthesis 453 (1972).
Anhydridmethode, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydrochinolin [Anhydride Methods, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline]: B. Belleau et al., J. Am. Chem. Soc., 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot. Res., 26: 493 (1985) and J. R. Voughn, Am. Soc. 73: 3547 (1951).
Imidazolid-Methode [Imidazolide Methods]: B. F. Gisin; R. B. Menifield; D. C. Tosteon, Am. Soc. 91: 2691 (1969).
Sxc3xa4urechlorid-Methoden, Thionylchlorid [Acid Chloride Methods, Thionyl Chloride]: Helv., 42: 1653 (1959).
Oxalylchlorid [Oxalyl Chloride]: J. Org. Chem., 29: 843 (1964).
As coupling adjuvants that are optionally to be used, all that are known to one skilled in the art are suitable (Houben-Weyl, Methoden der organischen Chemie, Volume XV/2, Georg Thieme-Verlag, Stuttgart, 1974). By way of example, 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, 3,5-dinitrophenol and pentafluorophenol can be mentioned. Preferred are 4-nitrophenol and N-hydroxysuccinimide; especially preferred in this case is the first-mentioned reagent.
The cleavage of the protective groups is carried out according to the processes that are known to one skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of esters with alkali in aqueous-alcoholic solution at temperatures of 0xc2x0 to 50xc2x0 C., acid saponification with mineral acids or in the case of, e.g., tert-butylesters with the aid of trifluoroacetic acid [Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. New York, 1991], in the case of benzyl ethers with hydrogen/palladium/carbon.
The production of the starting material, the compounds of Formula IIIb, 
is known from DE 196 52 386.
The amines of general formula IVb 
are commercially available products (Fluorochem, ABCR) or can be obtained according to the following process from compounds of general formula Vb by reaction with an amine of general formula VIb and subsequent reduction of the compounds of general formula VIIb: 
in which
RF, A1, L1 and R3 have the above-mentioned meaning, and Lxe2x80x2 has the meaning of group L1, in which the xcex1-CH2-group is still missing, and
R9 stands for hydrogen or a methyl group.
According to the process described in the literature that was already disclosed above for the activation of carboxylic acid IIIb, acid Vb is activated with amine VIb before the reaction. For R9 in the meaning of a methyl group, an aminolysis is performed.
The compounds of general formula Vb are commercially available products (Fluorochem, ABCR) or are produced as disclosed in DE 196 03 033.
The compounds of general formula VIb are commercially available products (Fluorochem, ABCR) or can be produced as described in Houben-Weyl, Methoden der organischen Chemie, XI/2 Stickstoffverbindungen [XI/2 Nitrogen Compounds], Georg Thieme Verlag Stuttgart, 1957, p. 680; J. E. Rickman and T. Atkins, Am. Chem. Soc., 96:2268, 1974, 96: 2268; F. Chavez and A. D. Sherry. J. Org. Chem. 1989, 54: 2990.
The compounds of general formula IVb are obtained in a way that is known in the art [Helv. Chim. Acta. 77: 23 (1994)] by reduction of the compounds of general formula VII, for example, with diborane or lithium aluminum hydride and cleavage of the protective groups.
Process B.
As starting material, the carboxylic acid of formula IIIx is used with R1 in the meaning of hydrogenxe2x80x94it still does not contain any metal ion equivalent R1. The carboxyl groups are protected according to the processes that are known to one skilled in the art, and a compound of Formula IIIy is obtained, whereby R5 stands for any protective group and R5xe2x80x2 stands for its precursor. 
As carboxyl protective groups, e.g., straight-chain or branched C1-C6 alkyl, aryl and aralkyl groups, for example, the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis(p-nitrophenyl)-methyl group and trialkylsilyl groups are suitable. The t-butyl group is preferred. 
The reaction of the protected carboxylic acid IIIy with the amine of formula IVb and the cleavage of the protective groups is carried out as described under process A and in a subsequent step, the obtained carboxylic acid Ix is reacted with at least one metal oxide or metal salt of an element of the desired atomic number as is disclosed in, e.g., DE 195 25 924.
If the metal complex that is obtained from process A or B still contains free COOH groups, these groups can also be present as salts of physiologically compatible inorganic or organic bases.
The neutralization of optionally still present free carboxy groups is then carried out with the aid of inorganic bases (for example, hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium, or calcium and/or organic bases such as, i.a., primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N,N-dimethylglucamine, as well as basic amino acids, such as, for example, lysine, arginine, and ornithine, or amides of originally neutral or acidic amino acids.
According to the invention, quite especially preferably metal complexes V, VII, VIII, IX and X (cf. Table 1) are used.
These compounds of general formula Ib are very well suited as MRI contrast media for visualization of plaque.
In another preferred embodiment of the invention, the perfluoroalkyl-containing complexes with sugar radicals of general formula Ic 
in which
R represents a mono-or oligosaccharide radical bonded by the 1-OHxe2x80x94 or 1-SH-position,
RF is a perfluorinated, straight-chain or branched carbon chain with the formula xe2x80x94CnF2nE, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for numbers 4-30,
K stands for a metal complex of general formula IIc, 
in which
R1 means a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70,
provided that at least two R1 stand for metal ion equivalents,
R2 and R3, independently of one another, represent hydrogen, C1-C7 alkyl, benzyl, phenyl, xe2x80x94CH2OH or xe2x80x94CH2OCH3, and
U represents xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2-xcfx89, xe2x80x94(CH2)1-5-xcfx89, a phenylene group, xe2x80x94CH2xe2x80x94NHCOxe2x80x94CH2xe2x80x94CH(CH2COOH)xe2x80x94C6H4-xcfx89, xe2x80x94C6H4xe2x80x94(OCH2CH2)0-1xe2x80x94N(CH2COOH)xe2x80x94CH2-xcfx89, or a C1-C12 alkylene group or C7-C12xe2x80x94C6H4xe2x80x94O group optionally interrupted by one or more oxygen atoms, 1 to 3 xe2x80x94NHCO groups or 1 to 3 xe2x80x94CONH groups and/or substituted with 1 to 3 xe2x80x94(CH2)0-5COOH groups, whereby xcfx89 stands for the binding site to xe2x80x94COxe2x80x94,
or
of general formula IIIc 
in which R1 has the above-mentioned meaning, R4 represents hydrogen or a metal ion equivalent mentioned under R1, and U1 represents xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2-xcfx89, whereby xcfx89 means the binding site to xe2x80x94COxe2x80x94,
or of general formula IVc 
in which R1 and R2 have the above-mentioned meaning
or of general formula VcA or VcB 
in which R1 has the above-mentioned meaning,
or of general formula VIc 
in which R1 has the above-mentioned meaning,
or of general formula VIIc 
in which R1 has the above-mentioned meaning, and
U1 represents xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2-xcfx89, whereby xcfx89 means the binding site to xe2x80x94COxe2x80x94 or of general formula VIIIc 
in which R1 has the above-mentioned meaning,
and in radical K, optionally present free acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides,
G for the case that K means metal complexes IIc to VIIc, represents a radical that is functionalized in at least three places and is selected from the following radicals a) to j) 
and
G for the case that K means metal complex VIIIc, represents a radical that is functionalized in at least three places and is selected from k) or l) 
whereby a means the binding site of G to complex K, xcex2 is the binding site of G to radical Y, and xcex3 represents the binding site of G to radical Z,
Y means xe2x80x94CH2, xcex4-(CH2)1-5CO-xcex2, xcex4-CH2xe2x80x94CHOHxe2x80x94CO-xcex2 or xcex4-CH(CHOHxe2x80x94CH2OH)xe2x80x94CHOHxe2x80x94CHOHxe2x80x94CO-xcex2, whereby xcex4 represents the binding site to sugar radical R, and xcex2 is the binding site to radical G,
Z stands for 
xcex3-COCH2xe2x80x94N(C2H5)xe2x80x94SO2-xcex5,
xcex3-COCH2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94SO2-xcex5, 
or
xcex3-NHCH2CH2xe2x80x94Oxe2x80x94CH2CH2-xcex5
whereby xcex3 represents the binding site of Z to radical G, and xcex5 means the binding site of Z to perfluorinated radical RF 
and
l1, m1, independently of one another, mean integer 1 or 2, and
p1 means integers 1 to 4,
can be used.
Since the compounds according to the invention are intended for use in NMR-diagnosis, the metal ion of the signaling group must be paramagnetic. These are especially the divalent and trivalent ions of the elements of atomic numbers 23-29, 42-46 and 58-70. Suitable ions are, for example, the chromium(III), iron(II), cobalt(II), nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(II) and ytterbium(III) ion. Because of their strong magnetic moment, gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), iron(III) and manganese(II) ions are especially preferred.
Preferred are manganese(II), iron(II), iron(III), praseodymium(III), neodymium(III), samarium(III), gadolinium(III) and ytterbium(III) ions, especially dysprosium(III) ions.
In R1, optionally present acidic hydrogen atoms, i.e., those that have not been substituted by the central ion, can optionally be replaced completely or partially by cations of inorganic and/or organic bases or amino acids or amino acid amides.
Suitable inorganic cations are, for example, the lithium ion, the potassium ion, the calcium ion and especially the sodium ion. Suitable cations of organic bases are, i.a., those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine, and ornithine as well as the amides of otherwise acidic or neutral amino acids.
Especially preferred compounds of general formula Ic are those with macrocyclic compound K of general formula IIc.
Radical U in metal complex K means preferably xe2x80x94CH2xe2x80x94 or C6H4xe2x80x94Oxe2x80x94CH2-xcfx89, whereby xcfx89 stands for the binding site to xe2x80x94COxe2x80x94.
Alkyl groups R2 and R3 in the macrocyclic compound of general formula IIc can be straight-chain or branched. By way of example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, and 1,2-dimethylpropyl can be mentioned. R2 and R3, independently of one another, preferably mean hydrogen or C1-C4-alkyl. In a quite especially preferred embodiment, R2 stands for methyl and R3 stands for hydrogen.
The benzyl group or phenyl group R2 or R3 in macrocyclic compound K of general formula IIc can also be substituted in the ring.
Radical R in general formula Ic means a mono- or oligosaccharide radical or thiosugar radical that is bonded via the 1-OHxe2x80x94 or 1-SH-position, whereby in this connection according to the invention, this can be a deoxy sugar, which contains an H atom instead of one or more OH groups. In a preferred embodiment of the invention, R means a monosaccharide radical with 5 or 6 C atoms, preferably glucose, mannose, galactose, ribose, arabinose or xylose or their deoxy sugars, such as, for example, 6-deoxygalactose (fucose) or 6-deoxymannose (rhamnose) or their thiosugars, whereby glucose, mannose and galactose are especially preferred.
Of the compounds of general formula Ic according to the invention, in addition those are preferred in which RF means xe2x80x94CnF2n+1. n preferably stands for numbers 4-15. Quite especially preferred are radicals xe2x80x94C4F9, xe2x80x94C6F13, xe2x80x94C8F17, xe2x80x94C12F25 and 13 C14F29 as well as the radicals of the compounds that are mentioned in the examples.
Radical G that is functionalized in at least three places in general formula Ic, which represents the xe2x80x9cskeleton,xe2x80x9d means lysine radical (a) or (b) in a preferred embodiment of the invention.
Y and Z mean the linkers indicated in general formula Ic, whereby independently of one another, radical 
is preferred for Z, and radical xcex4-CH2CO-xcex2 is preferred for Y.
The perfluoroalkyl-containing metal complexes with sugar radicals of general formula Ic 
with K in the meaning of a metal complex of general formulas IIc to VIIc and G in the meaning of formulas a) to j), whereby Y, Z, R, RF, m1, p1 and l1 have the above-mentioned meaning, are produced by a carboxylic acid of general formula IIi 
in which R5 means a metal ion equivalent of atomic numbers 23-29, 42-46, or 58-70 or a carboxyl protective group, and R2, R3 and U have the above-mentioned meaning,
or a carboxylic acid of general formula IIIi 
in which R4, R5 and U1 have the above-mentioned meaning
or a carboxylic acid of general formula IVi 
in which R5 and R2 have the above-mentioned meaning
or a carboxylic acid of general formula Vi or Vii 
in which R5 has the above-mentioned meaning
or a carboxylic acid of general formula VIi 
in which R5 has the above-mentioned meaning
or a carboxylic acid of general formula VIIi 
in which R5 and U1 have the above-mentioned meanings, being reacted in a way that is known in the art in optionally activated form with an amine of general formula IXc 
in which G has the meaning of formulas a) to j), and R, RF, Y, Z, m1 and p1 have the indicated meaning, in a coupling reaction and optionally subsequent cleavage of optionally present protective groups to form a metal complex of general formula Ic or
if R5 has the meaning of a protective group, after cleavage of these protective groups in a subsequent step being reacted in a way that is known in the art with at least one metal oxide or metal salt of an element of atomic numbers 23-29, 42-46 or 58-70, and then, if desired, optionally present acidic hydrogen atoms being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides.
The compounds of general formula Ic according to the invention with K in the meaning of a metal complex of general formula VIIIc and G in the meaning of formulas k) or l) are produced by an amine of general formula VIIIi 
in which R5 means a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70 or a carboxyl protective group,
being reacted in a way that is known in the art with an optionally activated carboxylic acid of general formula Xc 
in which G has the meaning of formula k) or l) and R, RF, Y, Z, m1 nand p1 have the indicated meanings, in a coupling reaction and optionally subsequent cleavage of optionally present protective groups to form a metal complex of general formula Ic or
if R5 has the meaning of a protective group, after cleavage of these protective groups in a subsequent step, being reacted in a way that is known in the art with at least one metal oxide or metal salt of an element of atomic numbers 23-29, 42-46 or 58-70, and then, if desired, optionally present acidic hydrogen atoms being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides.
The carboxylic acids of general formulas IIi to VIIi that are used are either known compounds or are produced according to the processes that are described in the examples. Thus, the production of carboxylic acids of general formula IIi is known from DE 196 52 386. The production of the carboxylic acids of general formula IVi can be found in DE 197 28 954.
A precursor for compounds of general formula VcA is the N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxycarbonylmethyl)-3,6-diaza-octanedioic acid, which is described in EP 263 059.
The compounds of general formula VcB are derived from the isomeric diethylenetriamine-pentaacetic acid, which binds via acetic acid on the center N atom. This DTPA is described in Patents DE 195 07 819 and DE 195 08 058.
Compounds of general formula VIc are derived from N-(carboxymethyl)-N-[2-(2,6-dioxo-4-morpholinyl)-ethyl]-glycine, whose production is described in J. Am. Oil. Chem. Soc. (1982), 59(2), 104-107.
Compounds of general formula VIIc are derived from the 1-(4-carboxymethoxybenzyl)ethylenediamine-tetraacetic acid, which is described in U.S. Pat. No. 4,622,420.
The perbenzylated sugar acids that are used as starting substances can be produced analogously to Lockhoff; Angew. Chem. 1998, 110 No. 24, p. 3634 ff. For example, the production of 1-O-acetic acid from perbenzyl-glucose is carried out over 2 stages, via trichloroacetimidate and reaction with hydroxyacetic acid ethyl ester, BF3-catalysis in THF and subsequent saponification with NaOH in MeOH/THF.
In a more advantageous process, the perbenzylated sugar acids that are used as starting substances can also be produced by the perbenzylated Ixe2x80x94OH-sugar being dissolved in a water-immiscible organic solvent and being reacted with an alkylating reagent of general formula XIc
Nu-Lxe2x80x94COO-Sgxe2x80x83xe2x80x83(XIc),
in which Nu means a nucleofuge, L is xe2x80x94(CH2)(1-5), xe2x80x94CH2xe2x80x94CHOHxe2x80x94, xe2x80x94CH(CHOHxe2x80x94CH2OH)xe2x80x94CHOHxe2x80x94CHOHxe2x80x94, and Sg represents a protective group, in the presence of a base and optionally a phase transfer catalyst. As a nucleofuge, for example, the radicals xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OTs, xe2x80x94OMs, xe2x80x94OSO2CF3, xe2x80x94OSO2C4F9 or xe2x80x94OSO2C8F17 can be contained in the alkylating reagent of general formula XIc.
The protective group is a common acid protective group. These protective groups are well known to one skilled in the art (Protective Groups in Organic Syntheses, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc., New York 1991).
The reaction according to the invention can be carried out at temperatures from 0-50xc2x0 C., preferably from 0xc2x0 C. to room temperature. The reaction times are 10 minutes to 24 hours, preferably 20 minutes to 12 hours.
The base is added either in solid form, preferably fine-powder, or as 10-70%, preferably 30-50%, aqueous solution. NaOH and KOH are used as preferred bases.
As organic, water-immiscible solvent, for example, toluene, benzene, CF3-benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or mixtures thereof can be used in the alkylating process according to the invention.
As phase-transfer catalysts, the quaternary ammonium or phosphonium salts or else crown ethers, such as, e.g., [15]-crown-5 or [18]-crown-6, that are known for this purpose are used in the process according to the invention. Quaternary ammonium salts with four identical or different hydrocarbon groups at the.cation, selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl, are preferably suitable. The hydrocarbon groups at the cation must be large enough to ensure good solubility of the alkylating reagent in the organic solvent. According to the invention, N(butyl)4+xe2x80x94Clxe2x88x92, N(butyl)4+xe2x80x94HSO4xe2x88x92, but also N(methyl)4+xe2x80x94Clxe2x88x92 are especially preferably used.
As quite especially preferred compounds of general formula Ic, metal complex XV of Table 1 (Example 1) according to the invention is used.
In another preferred embodiment of the invention, the perfluoroalkyl-containing complexes with polar radicals of general formula Id are used 
in which
RF is a perfluorinated, straight-chain or branched carbon chain with formula xe2x80x94CnF2nE, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for numbers 4-30,
K stands for a metal complex of general formula IId, 
in which
R1 means a hydrogen atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70, provided that at least two R1 stand for metal ion equivalents,
R2 and R3, independently of one another, represent hydrogen, C1-C7-alkyl, benzyl, phenyl, xe2x80x94CH2OH or xe2x80x94CH2OCH3, and
U represents xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2-xcfx89-, xe2x80x94(CH2)1,5-xcfx89, a phenylene group, xe2x80x94CH2xe2x80x94NHCOxe2x80x94CH2xe2x80x94CH(CH2COOH)xe2x80x94C6H4-xcfx89-, xe2x80x94C6H4xe2x80x94(OCH2CH2)0-1xe2x80x94N(CH2COOH)xe2x80x94CH2-xcfx89, or a C1-C12-alkylene group or C7-C12xe2x80x94C6H4xe2x80x94O group optionally interrupted by one or more oxygen atoms, 1 to 3 xe2x80x94NHCO groups, 1 to 3 xe2x80x94CONH groups and/or substituted with 1 to 3 xe2x80x94(CH2)0-5COOH groups, whereby xcfx89 stands for the binding site to xe2x80x94COxe2x80x94,
or
of general formula IIId 
in which R1 has the above-mentioned meaning, R4 represents hydrogen or a metal ion equivalent mentioned under R1, and U1 represents xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2-xcfx89-, whereby xcfx89 means the binding site to xe2x80x94COxe2x80x94,
or of general formula IVd 
in which R1 and R2 have the above-mentioned meaning,
or of general formula VdA or VdB 
in which R1 has the above-mentioned meaning,
or of general formula VId 
in which R1 has the above-mentioned meaning,
or of general formula VIId 
in which R1 has the above-mentioned meaning, and
U1 represents xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2-xcfx89-, whereby xcfx89 means the binding site to xe2x80x94COxe2x80x94,
and in radical K, optionally present free acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides,
G represents a radical that is functionalized in at least three places and is selected from the following radicals a) to g) 
whereby xcex1 means the binding site of G to complex K, xcex2 is the binding site of G to radical R, and xcex3 represents the binding site of G to radical Z
Z stands for 
xcex3-C(O)CH2O(CH2)2-xcex5,
whereby xcex3 represents the binding site of Z to radical G and xcex5 means the binding site of Z to perfluorinated radical RF,
R represents a polar radical that is selected from complexes K of general formulas IId to VIId, whereby R1 here means a hydrogen atom or a metal ion equivalent of atomic numbers 20, 23-29, 42-46 or 58-70,
and radicals R2, R3, R4, U and U1 have the above-indicated meaning,
or
the folic acid radical
or
R means a carbon chain with 2-30 C atoms that is bonded to radical G via xe2x80x94COxe2x80x94 or SO2xe2x80x94 and is straight or branched, saturated or unsaturated, optionally interrupted by 1-10 oxygen atoms, 1-5 xe2x80x94NHCO groups, 1-5 xe2x80x94CONH groups, 1-2 sulfur atoms, 1-5 xe2x80x94NH groups or 1-2 phenylene groups, which optionally can be substituted with 1-2 OH groups, 1-2 NH2 groups, 1-2 xe2x80x94COOH groups, or 1-2 xe2x80x94SO3H groups,
or
optionally substituted with 1-8 OH groups, 1-5 xe2x80x94COOH groups, 1-2 SO3H groups, 1-5 NH2 groups, 1-5 C1-C4-alkoxy groups, and
l1, m1, p2, independently of one another, mean integer 1 or 2.
Since the compounds according to the invention are intended for use in NMR diagnosis, the metal ion of the signaling group must be paramagnetic. These are in particular the divalent and trivalent ions of the elements of atomic numbers 23-29, 42-46 and 58-70. Suitable ions are, for example, the chromium(III), iron(II), cobalt(II), nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(III) and ytterbium(III) ions. Because of their strong magnetic moment, gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), iron(III) and manganese(II) ions are especially preferred.
Preferred are manganese(II), iron(II), iron(III), praseodymium(III), neodymium(III), samarium(III), gadolinium(III) and ytterbium(III) ions, especially dysprosium(III) ions.
In R1, optionally present acidic hydrogen atoms, i.e., those that have not been substituted by the central ion, can be replaced optionally completely or partially by cations of inorganic and/or organic bases or amino acids or amino acid amides.
Suitable inorganic cations are, for example, the lithium ion, the potassium ion, the calcium ion and especially the sodium ion. Suitable cations of organic bases are, i.a., those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine, and especially N-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine, and ornithine as well as the amides of otherwise acidic or neutral amino acids.
Especially preferred compounds of general formula Id are those with macrocyclic compound K of general formulas IId, IIId, VdB or VIId.
Radical U in metal complex K preferably means xe2x80x94CH2xe2x80x94 or C6H4xe2x80x94Oxe2x80x94CH2-xcfx89, whereby xcfx89 stands for the binding site to xe2x80x94COxe2x80x94.
Alkyl groups R2 and R3 in the macrocyclic compound of general formula IId can be straight-chain or branched. By way of example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, and 1,2-dimethylpropyl can be mentioned. R2 and R3, independently of one another, preferably mean hydrogen or C1-C4-alkyl.
In a quite especially preferred embodiment, R2 stands for methyl and R3 stands for hydrogen.
The benzyl group or phenyl group R2 or R3 in macrocyclic compound K of general formula IId can also be substituted in the ring.
In a preferred embodiment, polar radical R in general formula Id means complex K, whereby the latter preferably in addition to a Gd3+- or Mn2+ complex also can be a Ca2+ complex. As polar radicals R, complexes K of general formulas IId, IIId, VdA or VIId are especially preferred. The latter as R1 quite especially preferably have a metal ion equivalent of atomic numbers 20, 25, 39 or 64.
In another preferred embodiment, polar radical R has the following meanings:
xe2x80x94C(O)CH2CH2SO3H
xe2x80x94C(O)CH2OCH2CH2OCH2CH2OH
xe2x80x94C(O)CH2OCH2CH2OH
xe2x80x94C(O)CH2OCH2CH(OH)CH2OH
xe2x80x94C(O)CH2NHxe2x80x94C(O)CH2COOH
xe2x80x94C(O)CH2CH(OH)CH2OH
xe2x80x94C(O)CH2OCH2COOH
xe2x80x94SO2CH2CH2COOH
xe2x80x94C(O)xe2x80x94C6H3-(m-COOH)2 
xe2x80x94C(O)CH2O(CH2)2xe2x80x94C6H3-(m-COOH)2 
xe2x80x94C(O)CH2Oxe2x80x94C6H4-m-SO3H
xe2x80x94C(O)CH2NHC(O)CH2NHC(O)CH2OCH2COOH
xe2x80x94C(O)CH2OCH2CH2OCH2COOH
xe2x80x94C(O)CH2OCH2CH(OH)CH2Oxe2x80x94CH2CH2OH
xe2x80x94C(O)CH2OCH2CH(OH)CH2OCH2xe2x80x94CH(OH)xe2x80x94CH2OH
xe2x80x94C(O)CH2SO3H
xe2x80x94C(O)CH2CH2COOH
xe2x80x94C(O)CH(OH)CH(OH)CH2OH
xe2x80x94C(O)CH2O[(CH2)2O]1-9xe2x80x94CH3 
xe2x80x94C(O)CH2O[(CH2)2O]1-9xe2x80x94H
xe2x80x94C(O)CH2OCH(CH2OH)2 
xe2x80x94C(O)CH2OCH(CH2OCH2COOH)2 
xe2x80x94C(O)xe2x80x94C6H3-(m-OCH2COOH)2 xe2x80x94COxe2x80x94CH2Oxe2x80x94(CH2)2O(CH2)2Oxe2x80x94(CH2)2O(CH2)2OCH3 
preferably xe2x80x94C(O)CH2O[(CH2)2O]4xe2x80x94CH3.
In another preferred embodiment, polar radical R means the folic acid radical.
Of the compounds of general formula Id according to the invention, in addition those are preferred in which RF means xe2x80x94CnF2n+1. n preferably stands for numbers 4-15. Quite especially preferred are the radicals xe2x80x94C4F9, xe2x80x94C6F13, xe2x80x94C8F17, xe2x80x94C12F25 and xe2x80x94C14F29.
Radical G that is functionalized in at least three places in general formula Id, which represents the xe2x80x9cskeleton,xe2x80x9d means lysine radical (a) or (b) in a preferred embodiment of the invention.
Z means the linker that is indicated in general formula Id, whereby radical 
is preferred.
The perfluoroalkyl-containing metal complexes with polar radicals of general formula Id 
in which K, G, R, Z, RF, I1, m1, and p2 have the above-indicated meaning, are produced by a carboxylic acid of general formula IIk 
in which R5 means a metal ion equivalent of atomic numbers 23-29, 42-46 or 58-70 or a carboxyl protective group, and R2, R3 and U have the above-mentioned meaning,
or a carboxylic acid of general formula IIIk 
in which R4, R5 and U1 have the above-mentioned meaning
or a carboxylic acid of general formula IVk 
in which R5 and R2 have the above-mentioned meaning
or a carboxylic acid of general formula Vk or Vm 
in which R5 has the above-mentioned meaning
or a carboxylic acid of general formula VIk 
in which R5 has the above-mentioned meaning
or a carboxylic acid of general formula VIIk 
in which R5 and U1 have the above-mentioned meanings,
being reacted in a way that is known in the art in optionally activated form with an amine of general formula VIIId 
in which G, R, Z, RF, m1 and p2 have the above-indicated meaning, in a coupling reaction and optionally subsequent cleavage of optionally present protective groups to form a metal complex of general formula Id or
if R5 has the meaning of a protective group, being reacted after cleavage of these protective groups in a subsequent step in a way that is known in the art with at least one metal oxide or metal salt of an element of atomic numbers 23-29, 42-46 or 58-70, and then, if desired, optionally present acidic hydrogen atoms being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides.
The carboxylic acids of general formulas IIk to VIIk that are used are either known compounds or are produced according to the processes that are described in the examples. Thus, the production of the carboxylic acids of general formula IIk is known from DE 196 52 386. The production of the carboxylic acids of general formula IVk can be found in DE 197 28 954.
A precursor of compounds of general formula VdA is the N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxycarbonylmethyl)-3,6-diaza-octanedioic acid, which is described in EP 263 059.
The compounds of general formula VdB are derived from the isomeric diethylenetriamine-pentaacetic acid, which binds via acetic acid on the center N-atom. This DTPA is described in Patents DE 195 07 819 and DE 195 08 058.
Compounds of general formula VId are derived from N-(carboxymethyl)-N-[2-(2,6-dioxo-4-morpholinyl)-ethyl]-glycine, whose production is described in J. Am. Oil. Chem. Soc. (1982), 59 (2), 104-107.
Compounds of general formula VIId are derived from 1-(4-carboxymethoxybenzyl)ethylenediamine-tetraacetic acid, whose production was described in U.S. Pat. No. 4,622,420.
Metal complex XVI of Table 1 according to the invention is used as a quite especially preferred compound of general formula Id.
In another preferred embodiment of the invention, galenical formulations can be used that contain paramagnetic and diamagnetic perfluoroallkyl-containing substances. The paramagnetic and diamagnetic substances are preferably present in a dissolved state in an aqueous solvent.
As paramagnetic, perfluoroalkyl-containing compounds, all above-mentioned metal complexes of general formulas I, Ia, Ib, Ic and/or Id according to the invention can be used in the formulations.
The diamagnetic perfluoroalkyl-containing substances are those of general formula XX:
RFxe2x80x94L2xe2x80x94B2xe2x80x83xe2x80x83(XX)
in which RF represents a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, L2 stands for a linker and B2 stands for a hydrophilic group. Linker L2 is a direct bond, an xe2x80x94SO2 group, or a straight-chain or branched carbon chain with up to 20 carbon atoms, which can be substituted with one or more xe2x80x94OH, xe2x80x94COOxe2x80x94, xe2x80x94SO3 groups and/or optionally contains one or more xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94CONR9xe2x80x94, xe2x80x94NR9COxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94PO4xe2x88x92xe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NR9 groups, an aryl ring or a piperazine, whereby R9 stands for a C1- to C20-alkyl radical, which in turn can contain one or more O atoms, and/or can be substituted with xe2x80x94COOxe2x88x92 or SO3 groups.
Hydrophilic group B2 is a mono- or disaccharide, one or more adjacent xe2x80x94COOxe2x88x92 or xe2x80x94SO3 groups, a dicarboxylic acid, an isophthalic acid, a picolinic acid, a benzenesulfonic acid, a tetrahydropyrandicarboxylic acid, a 2,6-pyridinedicarboxylic acid, a quaternary ammonium ion, an aminopolycarboxylic acid, an aminodipolyethylene glycolsulfonic acid, an aminopolyethylene glycol group, an SO2xe2x80x94(CH2)2xe2x80x94OH group, a polyhydroxyalkyl chain with at least two hydroxyl groups or one or more polyethylene glycol chains with at least two glycol units, whereby the polyethylene glycol chains are terminated by an xe2x80x94OH or xe2x80x94OCH3 group. Such substances are partially already known; such substances for the production of formulations according to the invention were partially newly synthesized. Known perfluoroalkyl-containing substances and their production are described in the following publications:
J. G. Riess, Journal of Drug Targeting, 1994, Vol. 2, pp. 455-468;
J. B. Nivet et al., Eur. J. Med. Chem., 1991, Vol. 26, pp. 953-960;
M.-P. Krafft et al., Angew. Chem., 1994, Vol. 106, No. 10, pp. 1146-1148;
M. Lanier et al., Tetrahedron Letters, 1995, Vol. 36, No. 14, pp. 2491-2492;
F. Guillod et al., Carbohydrate Research, 1994, Vol. 261, pp. 37-55;
S. Achilefu et al., Journal of Fluorine Chemistry, 1995, Vol. 70, pp.19-26;
L. Clary et al., Tetrahedron, 1995, Vol. 51, No. 47, pp. 13073-13088;
F. Szoni et al., Journal of Fluorine Chemistry, 1989, Vol. 42, pp. 59-68;
H. Wu et al., Supramolecular Chemistry, 1994, Vol.3, pp. 175-180;
F. Guileri et al., Angew. Chem. 1994, Vol. 106, No. 14, pp. 1583-1585;
M.-P. Krafft et al., Eur. J. Med. Chem., 1991, Vol. 26, pp.545-550;
J. Greiner et al., Journal of Fluorine Chemistry, 1992, Vol. 56, pp. 285-293;
A. Milius et al., Carbohydrate Research, 1992, Vol. 229, pp. 323-336;
J. Riess et al., Colloids and Surfaces A, 1994, Vol. 84, pp. 33-48;
G. Merhi et al., J. Med. Chem., 1996, Vol. 39, pp. 4483-4488;
V. Cirkva et al., Journal of Fluorine Chemistry, 1997, Vol. 83, pp. 151-158;
A. Ould Amanetoullah et al., Journal of Fluorine Chemistry, 1997, Vol. 84, pp. 149-153;
J. Chen et al., Inorg. Chem., 1996, Vol. 35, pp. 1590-161;
L. Clary et al., Tetrahedron Letters, 1995, Vol. 36, No. 4, pp.539-542;
M. M. Chaabouni ct al., Journal of Fluorine Chemistry, 1990, Vol. 46, pp.307-315;
A. Milius et al., New J. Chem., 1991, Vol. 15, pp.337-344;
M.-P. Krafft et al., New J. Chem., 1990, Vol. 14, pp. 869-875;
J.-B. Nivet et al., New J. Chem., 1994, Vol. 18, pp. 861-869;
C. Santaella et al., New J. Chem., 1991, Vol. 15, pp. 685-692;
C. Santaella et al., New J. Chem., 1992, Vol. 16, pp. 399-404;
A. Milius et al., New J. Chem., 1992, Vol. 16, pp. 771-773;
F. Szxc3x6nyi et al., Journal of Fluorine Chemistry, 1991, Vol. 55, pp. 85-92;
C. Santaella et al., Angew. Chem., 1991, Vol. 103, No. 5, pp. 584-586;
M.-P. Krafft et al., Angew. Chem., 1993, Vol. 105, No. 5, pp. 783-785;
EP 0 548 096 B1.
The production of the new perfluoroalkyl-containing substances is carried out analogously to the above-mentioned compounds that are known in the literature and is described in the examples. In this case, these are substances of general formula XXI
RFxe2x80x94X1xe2x80x83xe2x80x83(XXI)
in which RF represents a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, and X1 is a radical that is selected from the group of the following radicals (n in this case is a number between 1 and 10): 
Preferred diamagnetic perfluoroalkyl-containing substances are those with a monosaccharide as hydrophilic group B2.
Especially preferred diamagnetic perfluoroalkyl-containing compounds contain a perfluoroalkyl radical Rf with 6 to 12 carbon atoms, a linker L2, which represents an xe2x80x94SO2 group, or a straight-chain or branched carbon chain with up to 20 carbon atoms, which in turn contains one or more xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94CONRxe2x80x94, xe2x80x94NRCOxe2x80x94, or xe2x80x94SO2 groups or a piperazine, in which R has the above-indicated meaning, and a monosaccharide as hydrophilic group B2.
Other suitable diamagnetic perfluoroalkyl-containing compounds are conjugates that consist of cyclodextrin and perfluoroalkyl-containing compounds. These conjugates consist of xcex1-, xcex2- or xcex3-cyclodextrin and compounds of general formula XXII
A1xe2x80x94L3xe2x80x94RFxe2x80x83xe2x80x83(XXII)
in which A1 stands for an adamantan, biphenyl or anthracene molecule, L3 stands for a linker, and RF stands for a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms. Linker L3 is a straight-chain hydrocarbon chain with 1 to 20 carbon atoms, which can be interrupted by one or more oxygen atoms, one or more COxe2x80x94, SO2xe2x80x94, CONHxe2x80x94, NHCOxe2x80x94, CONRxe2x80x94, NRCOxe2x80x94, NHxe2x80x94 or NR groups or a piperazine, whereby R is a C1-C5-alkyl radical.
Preferred compounds are the following compounds: 
The galenical formulations of this invention contain the paramagnetic and diamagnetic perfluoroalkyl-containing compounds in a mixing ratio of between 5:95 and 95:5. Preferred are mixing ratios of between 40:60 and 60:40 of the two substances. Both substances are used in millimolar concentrations. Concentrations of between 0.5 and 1000 mmol/l of solvent are achieved. The solvent is preferably water. The metal concentration of the formulations is preferably in a range of 50-250 mmol/l.
Preferred are mixtures that consist of paramagnetic and diamagnetic perfluoroalkyl-containing compounds, in which the perfluoroalkyl chains have a length of 6 to 12 carbon atoms. Especially preferred are mixtures in which both the paramagnetic and the diamagnetic perfluoroalkyl-containing compounds have a perfluoroalkyl chain with 8 carbon atoms.
The production of the galenical formulations is carried out in that the paramagnetic perfluoroalkyl-containing compounds (components A) and the diamagnetic perfluoroalkyl-containing substances (components B) are weighed in fractions of a mol of between 0.05 and 0.95 in components A or B and are dissolved in a suitable solvent. An especially well suited solvent is water. Common galenical additives, such as, e.g., buffer solutions and the Ca-salt of the complexing agent, are then added in excess to this solution. At 10 to 100xc2x0 C., the solutions are stirred vigorously. As an alterative, the solutions can be treated in an ultrasound bath at 10 to 100xc2x0 C. Another alternative consists in that the solutions are treated with microwaves.
In substances that do not dissolve in water as individual components, it proves advantageous to add a solubilizer such as alcohol (e.g., methanol or ethanol) or another water-miscible solvent, and the latter can then be distilled off slowly. The distillation can be carried out under a vacuum. The residue is then dissolved in water, and the solution is filtered. It is also possible to dissolve each component separately in one solvent each, then to combine them and proceed as indicated above. It has proven advantageous to introduce a relatively strongly concentrated solution ( greater than 100 mmol) of the metal complex (component A) and then to add component B in the pure state, and, as mentioned above, to stir the solution or to treat it with ultrasound or microwaves.
In summary, it has been determined that as quite especially preferred compounds, gadolinium complexes I-XVI that are presented in Table 1 meet the criteria according to the invention. The physical parameters of these metal complexes I-XVI are presented in Table 2.
Both the paramagnetic compounds of general formulas I, Ia, Ib, Ic and Id according to the invention and the formulations that consist of paramagnetic and diamagnetic perfluoroalkyl-containing substances according to the invention are extremely well suited as contrast media in MR-imaging for visualization of plaque, tumors and necroses.